Oral patch platform based on multi-mechanism synergy and micro-matrix controlled release and preparation method thereof

Abstract

The invention discloses an oral patch platform based on multi-mechanism synergy and micro-matrix controlled release and a preparation method thereof. The patch comprises core nutrients (such as iron, calcium, folic acid and zinc) and a synergistic nutrient system (such as vitamin C, vitamin D, vitamin B12 and copper), and the release kinetics of different nutrients are accurately regulated and controlled through a physically separated multi-cavity structure (such as a double-semicircular laminated sheet) or a unique hydrophilic-hydrophobic micro-matrix component design; the effects of synergistically promoting absorption, assisting metabolism or preventing antagonism are achieved. According to the invention, the first-pass effect of the liver is avoided through oral mucosa absorption, and the composition can be attached to multiple sites in the oral cavity, so that the absorption efficiency, the bioavailability and the supplement safety of target nutrients are remarkably improved, and the composition is suitable for developing a series of nutritional supplement products or medicine products.

Description

TECHNICAL FIELD

[0002] The present application relates to the field of functional food, nutritional supplement and drug delivery system, in particular to a sustained-release patch platform which can be attached to multiple sites in the oral cavity (such as sublingual, buccal mucosa, gums, palate), and through the control of the release kinetics of nutrients with synergistic or antagonistic effects, to systematically improve the absorption efficiency, bioavailability and safety. BACKGROUND

[0003] The public demand for precise and efficient nutritional supplements is growing. Traditional oral nutritional supplements (such as tablets, capsules) have low bioavailability, gastrointestinal irritation, unsatisfactory release profile, and swallowing difficulties. More importantly, the oral route has a 'first-pass effect' in the liver, that is, after the nutrient is absorbed by the gastrointestinal tract, it needs to pass through the portal vein into the liver, where it is largely metabolized and broken down, resulting in a significant reduction in the effective dose that actually enters the systemic circulation.

[0004] There are some oral patches in the prior art, but their design goals are mainly focused on treating oral ulcers or delivering specific drugs. These patches mostly use fast-dissolving technology, aiming to quickly release the drug for local treatment, which is completely different from the goal of the present application of'systematic nutritional supplementation' and 'long-acting sustained release'.

[0005] In addition, it is known in nutrition that there are synergistic absorption or antagonistic effects between many nutrients (such as vitamin C promoting iron absorption, zinc and copper competing for absorption). However, in traditional dosage forms, these complex interactions cannot be effectively and controllably managed. Therefore, there is an urgent need in the art for a new oral delivery system that can avoid the first-pass effect in the liver and achieve efficient synergistic supplementation of nutrients through precise spatiotemporal control. SUMMARY

[0006] The present application aims to overcome the shortcomings of the prior art and provide a platformized sustained-release patch that can avoid the first-pass effect in the liver, be attached to multiple sites in the oral cavity, and achieve synergistic enhancement of nutrients through unique micro-matrix controlled-release technology, as well as a preparation method thereof.

[0007] The patch delivers nutrients through the oral mucosa absorption pathway. After the active ingredients are absorbed through the mucosa, they directly enter the systemic circulation system under the mucosa (through the jugular vein), rather than entering the liver through the portal vein. This path completely avoids the first-pass metabolism of the liver physiologically, allowing more undegraded active ingredients to reach the whole body, thereby significantly improving the bioavailability of nutrients.

[0008] The patch comprises a core nutrient and a synergistic nutrient system configured to enhance the bioavailability or physiological function of the core nutrient through at least one mechanism of promoting absorption, assisting metabolism or preventing antagonism. Preferred combinations include but are not limited to iron with vitamin C, calcium with vitamin D, folate with vitamin B12, and zinc with copper (in a 5:1 to 15:1 ratio).

[0009] The patch is a physically separated multi-chambered structure, such as a double half-circular compressed tablet. The first chamber contains the core nutrient and the second chamber contains at least one nutrient in the synergistic nutrient system. The two chambers are configured to have independent release kinetics, for example, the synergistic nutrient (such as vitamin C) can be released quickly to create an absorption environment, while the core nutrient (such as iron) is released slowly and continuously, achieving precise synergy in timing.

[0010] The patch is made of a composition comprising: a) Active ingredients: the core nutrient and the synergistic nutrient system; b) Film-forming matrix: a mixture comprising a hydrophilic film-forming polymer (such as hydroxypropyl methylcellulose HPMC) and a hydrophobic component (such as ethyl cellulose EC); c) Multi-site adhesion and residence enhancer: selected from one or more of colloidal silicon dioxide, microcrystalline cellulose, carbomer, xanthan gum.

[0011] Mechanism explanation: When the patch is placed in a moist oral environment, the hydrophilic polymer (such as HPMC) rapidly hydrates and swells to form a gel skeleton; while the hydrophobic particles (such as EC) act as "micro-zone barriers" that are insoluble in water, hindering the rapid penetration of water and the free diffusion of nutrients. Water and nutrients must bypass these hydrophobic barriers and slowly enter and exit through the tortuous gel channels. By adjusting the ratio and type of hydrophilic and hydrophobic components, the dissolution rate of the entire patch and the diffusion speed of the nutrients can be precisely controlled like a program, achieving long-acting, smooth release from half an hour to several hours, which is fundamentally different from fast-dissolving patches.

[0012] Method 1: dry powder compression and compounding (suitable for multi-chambered tablets) Prepare powder mixtures for different chambers respectively; Use a specially designed multi-chambered tablet press die to compress the powders in different chambers into a complete, physically separated tablet in one compression process.

[0013] Method 2: hot melt extrusion-roller film formation (suitable for film agents, which can better form uniform micro-matrix) After pre-mixing the components, melt and blend them through a hot melt extruder at a specific temperature; The extruded hot melt is pressed into a uniform film by a calender roller; Cooling and punching into shape.

[0014] High bioavailability: absorbed through the oral mucosa, fundamentally avoiding the liver first-pass effect, ensuring efficient use of nutrients.

[0015] Precise synergistic effect: through the multi-chamber structure and independent release kinetics design, the synergistic nutrients are optimized in time and space, achieving an absorption effect of "1+1>2".

[0016] Persistent and stable release: the unique "hydrophilic-hydrophobic micro-matrix" structure ensures long-term and stable release in the oral neutral environment, providing a good user experience.

[0017] Platform design: a single technology platform can derive a variety of products such as iron supplementation, calcium supplementation, and B vitamin supplementation, with wide application.

[0018] Safe and non-irritating: avoiding the gastrointestinal tract, non-irritating.

[0019] Simple and environmentally friendly process: the method does not require organic solvents and is suitable for industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0020] Figure 1 shows the structure of a double half-round compression tablet. Figure 1

[0021] Figure 2 shows the structure of a double-layer film. Figure 2 DETAILED DESCRIPTION

[0024] The application will be further described below through examples, but not used to limit the scope of the application. Example 1: Iron-Vitamin C synergistic release double half-round compression tablet Structure: double half-round compression tablet, total diameter 5mm.

[0025] A half tablet (Vitamin C release-promoting layer): Vitamin C 60mg, mannitol 80mg, cross-linked povidone 10mg, hydroxypropyl cellulose 5mg.

[0026] B half tablet (iron release-retarding layer): ferrous fumarate (elemental iron 10mg) 30mg, hydroxypropyl methylcellulose (HPMC K4M) 60mg, microcrystalline cellulose 20mg.

[0027] Preparation: Mix A and B half tablet powders separately, and use a double-cavity tablet compression mold to form a one-time compression.

[0028] Release characteristics: A half tablet releases Vitamin C rapidly within 15-60 minutes; B half tablet releases iron slowly within the next 2-4 hours.

[0029] ​​Formulation: Calcium carbonate (elemental calcium 100 mg) 250 mg, Vitamin D3 400 IU, Vitamin K2 (MK-7) 50 μg, HPMC 150 mg, Ethyl cellulose (granules) 50 mg, Colloidal silicon dioxide 80 mg, Glycerin (plasticizer) 20 mg.

[0030] Preparation: Hot melt extrusion method (100 °C) was used, and the extrudate was rolled into a film and punched into 10 mm x 10 mm squares.

[0031] Release profile: All active ingredients were released synchronously and continuously within 4-6 hours.

[0032] Formulation (single layer film): Folic acid 400 μg, Vitamin B12 (cyanocobalamin) 10 μg, HPMC 100 mg, Microcrystalline cellulose 50 mg.

[0033] Preparation: Dry powder tabletting method was used.

[0034] Release profile: Folic acid and B12 were released synchronously in a fixed ratio within 2-3 hours.

[0035] Structure: Double half-circular compressed tablets.

[0036] A half tablet (zinc sustained release layer): Amino acid chelated zinc (elemental zinc 15 mg), HPMC 60 mg.

[0037] B half tablet (copper sustained release layer): Amino acid chelated copper (elemental copper 1.5 mg), HPMC 60 mg.

[0038] Preparation: Same as Example 1.

[0039] Release profile and effect: The two layers were released synchronously at the same rate for 2-4 hours, maintaining a Zn:Cu absorption ratio of 10:1, and safely and effectively supplementing zinc.

[0040] Effect experimental example: In vitro release rate determination of Example 1 and conventional iron-Vitamin C compound tablets in a simulated oral environment. The results showed that Example 1 achieved the designed sequential-sustained release characteristics, while the comparative example was rapidly and synchronously released. Further animal experiments (iron deficiency anemia model rats) showed that the hemoglobin recovery rate of rats fed with Example 1 tablets was significantly better than that of the comparative example group (P<0.05), proving the superiority of the synergistic effect.

[0041] A nutrient synergistic oral sustained-release patch, characterized in that the patch comprises a core nutrient and a synergistic nutrient system; the patch is made of a composition comprising: a) Active ingredients: the core nutrient and the synergistic nutrient system; b) film-forming base: a mixture comprising a hydrophilic film-forming polymer and a hydrophobic component; c) multi-site adhesion and residence enhancer; wherein the hydrophobic component is dispersed in the form of solid particles in the hydrophilic film-forming polymer, forming a heterogeneous hydrophilic-hydrophobic micro-matrix.

[0042] The oral sustained-release patch of claim 1, wherein the synergistic nutrient system is configured to enhance bioavailability or physiological function of the core nutrient by at least one mechanism of promoting absorption, assisting metabolism, or preventing antagonism.

[0043] The oral sustained-release patch of claim 1 or 2, wherein the combination of the core nutrient and the synergistic nutrient system is any one of the following combinations: (a) the core nutrient is iron, and the synergistic nutrient system comprises vitamin C; (b) the core nutrient is calcium, and the synergistic nutrient system comprises vitamin D; (c) the core nutrient is folic acid, and the synergistic nutrient system comprises vitamin B12; (d) the core nutrient is zinc, and the synergistic nutrient system comprises copper.

[0044] The oral sustained-release patch of claim 3, wherein in the combination (a), the synergistic nutrient system further comprises one or more of vitamin A, vitamin B2, an organic acid, or an amino acid.

[0045] The oral sustained-release patch of claim 3, wherein in the combination (b), the synergistic nutrient system further comprises vitamin K2.

[0046] The oral sustained-release patch of claim 3, wherein in the combination (d), the mass ratio of zinc to copper is from 5: 1 to 15: 1.

[0047] The oral sustained-release patch of claim 1, wherein the patch is a physically partitioned multi-chamber structure, wherein a first chamber comprises the core nutrient, a second chamber comprises at least one nutrient in the synergistic nutrient system, and the two chambers are configured to have independent release kinetics.

[0048] The oral sustained-release patch of claim 7, wherein the multi-chamber structure is a double half-circular compressed tablet.

[0049] The oral sustained-release patch according to claim 1 is characterized in that the hydrophilic film-forming polymer is selected from one or more of hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose (HEC), polyvinylpyrrolidone (PVP), and sodium alginate.

[0050] The oral sustained-release patch according to claim 1, wherein the hydrophobic component is selected from one or more of ethyl cellulose, mono- and diglycerides, fatty acids, and hydrogenated vegetable oils.

[0051] The oral sustained-release patch as described in claim 1 is characterized in that the multi-site adhesion and retention enhancer is selected from one or more of colloidal silica, microcrystalline cellulose, carbomer, and xanthan gum.

[0052] A method for preparing an oral sustained-release patch as described in any one of claims 1-11, characterized in that the method is a dry powder compression and compounding process.

[0053] A method for preparing an oral sustained-release patch as described in any one of claims 1-11, characterized in that the method is a hot melt extrusion-roll forming process.

[0054] Use of the oral sustained-release patch as described in any one of claims 1-11 in the preparation of functional foods for systematically supplementing nutrients via the oral mucosa.

Claims

1. A nutrient-synergistic sustained-release oral patch, characterized in that, The patch contains a core nutrient and a synergistic nutrient system; the patch is made from a composition comprising the following components: a) Active ingredients: the core nutrients and synergistic nutrient system; b) Film-forming matrix: a mixture containing hydrophilic film-forming polymers and hydrophobic components; c) Multi-site adhesion and retention enhancers; The hydrophobic component is dispersed in the hydrophilic film-forming polymer in the form of solid particles, forming a heterogeneous hydrophilic-hydrophobic micromatrix.

2. The oral sustained-release patch as described in claim 1, characterized in that, The synergistic nutrient system is configured to enhance the bioavailability or physiological function of the core nutrient through at least one mechanism, such as promoting absorption, aiding metabolism, or preventing antagonism.

3. The oral sustained-release patch as described in claim 1 or 2, characterized in that, The combination of the core nutrient and synergistic nutrient system is any of the following combinations: (a) The core nutrient is iron, and the synergistic nutrient system includes vitamin C; (b) The core nutrient is calcium, and the synergistic nutrient system includes vitamin D; (c) The core nutrient is folic acid, and the synergistic nutrient system includes vitamin B12; (d) The core nutrient is zinc, and the synergistic nutrient system includes copper.

4. The oral sustained-release patch as described in claim 3, characterized in that, In combination (a), the synergistic nutrient system further comprises one or more of vitamin A, vitamin B2, organic acids, or amino acids.

5. The oral sustained-release patch as described in claim 3, characterized in that, In combination (b), the synergistic nutrient system further includes vitamin K2.

6. The oral sustained-release patch as described in claim 3, characterized in that, In the combination (d), the mass ratio of zinc to copper is from 5:1 to 15:

1.

7. The oral sustained-release patch as described in claim 1, characterized in that, The patch is a physically separated multi-chamber structure, wherein the first chamber contains the core nutrient, the second chamber contains at least one nutrient from the synergistic nutrient system, and the two chambers are configured to have independent release kinetics.

8. The oral sustained-release patch as described in claim 7, characterized in that, The multi-chamber structure is a double semi-circular compressed tablet.

9. The oral sustained-release patch as described in claim 1, characterized in that, The hydrophilic film-forming polymer is selected from one or more of hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose (HEC), polyvinylpyrrolidone (PVP), and sodium alginate.

10. The oral sustained-release patch as described in claim 1, characterized in that, The hydrophobic component is selected from one or more of ethyl cellulose, mono- and diglycerides, fatty acids, and hydrogenated vegetable oils.

11. The oral sustained-release patch as described in claim 1, characterized in that, The multi-site adhesion and retention enhancer is selected from one or more of colloidal silica, microcrystalline cellulose, carbomer, and xanthan gum.

12. A method for preparing an oral sustained-release patch as described in any one of claims 1-11, characterized in that, The method is a dry powder compression and compounding process.

13. A method for preparing an oral sustained-release patch as described in any one of claims 1-11, characterized in that, The method is a hot melt extrusion-roll forming process.

14. Use of the oral sustained-release patch as described in any one of claims 1-11 in the preparation of functional foods for the systematic supplementation of nutrients via the oral mucosa.

Images